TACC2 Is an Androgen-Responsive Cell Cycle Regulator Promoting Androgen-Mediated and Castration-Resistant Growth of Prostate Cancer

ArticleinMolecular Endocrinology 26(5):748-61 · March 2012with12 Reads
DOI: 10.1210/me.2011-1242 · Source: PubMed
Despite the existence of effective antiandrogen therapy for prostate cancer, the disease often progresses to castration-resistant states. Elucidation of the molecular mechanisms underlying the resistance for androgen deprivation in terms of the androgen receptor (AR)-regulated pathways is a requisite to manage castration-resistant prostate cancer (CRPC). Using a ChIP-cloning strategy, we identified functional AR binding sites (ARBS) in the genome of prostate cancer cells. We discovered that a centrosome- and microtubule-interacting gene, transforming acidic coiled-coil protein 2 (TACC2), is a novel androgen-regulated gene. We identified a functional AR-binding site (ARBS) including two canonical androgen response elements in the vicinity of TACC2 gene, in which activated hallmarks of histone modification were observed. Androgen-dependent TACC2 induction is regulated by AR, as confirmed by AR knockdown or its pharmacological inhibitor bicalutamide. Using long-term androgen-deprived cells as cellular models of CRPC, we demonstrated that TACC2 is highly expressed and contributes to hormone-refractory proliferation, as small interfering RNA-mediated knockdown of TACC2 reduced cell growth and cell cycle progression. By contrast, in TACC2-overexpressing cells, an acceleration of the cell cycle was observed. In vivo tumor formation study of prostate cancer in castrated immunocompromised mice revealed that TACC2 is a tumor-promoting factor. Notably, the clinical significance of TACC2 was demonstrated by a correlation between high TACC2 expression and poor survival rates. Taken together with the critical roles of TACC2 in the cell cycle and the biology of prostate cancer, we infer that the molecule is a potential therapeutic target in CRPC as well as hormone-sensitive prostate cancer.
    • "The multitude of ways that TACC3 impacts development—cell cycle regulation, microtubule dynamicity, organized migration, and possibly hypoxia—merit further investigation in the context of WHS. It is worth noting that paralogous proteins TACC1 and TACC2 have been implicated in certain carcinomas, and thus could also impact migration (Conte et al., 2003; Gangisetty et al., 2004; Kimura and Okano, 2005; Takayama et al., 2012). Recently, TACC1 and TACC2 were revealed to possess plus-tip-tracking activity and the ability to influence MT dynamics in a manner similar to TACC3 (Lucaj et al., 2015; Rutherford et al., 2016). "
    [Show abstract] [Hide abstract] ABSTRACT: Wolf-Hirschhorn syndrome (WHS) is a neurodevelopmental disorder characterized by mental retardation, craniofacial malformation, and defects in skeletal and heart development. The syndrome is associated with irregularities on the short arm of chromosome 4, including deletions of varying sizes and microduplications. Many of these genotypic aberrations in humans have been correlated with the classic WHS phenotype, and animal models have provided a context for mapping these genetic irregularities to specific phenotypes; however, there remains a significant knowledge gap concerning the cell biological mechanisms underlying these phenotypes. This review summarizes literature that has made recent contributions to this topic, drawing from the vast body of knowledge detailing the genetic particularities of the disorder and the more limited pool of information on its cell biology. Finally, we propose a novel characterization for WHS as a pathophysiology owing in part to defects in neural crest cell motility and migration during development.
    Full-text · Article · Oct 2016
    • "In contrast, in HeLa cells, loss of TACC2 centrosomal localization led to defects in mitotic spindle function (Dou et al., 2004). In addition, later studies of TACC2 suggested that it can function as both a tumor suppressor and an oncogenic protein (Cheng et al., 2010; Lauffart et al., 2003; Takayama et al., 2012), raising the idea that the requirement and function of TACC2 might vary between cell types and model systems. Furthermore, it has been suggested that the three TACC family proteins might exhibit differing degrees of functional redundancy (Gergely et al., 2000; Sadek et al., 2003). "
    [Show abstract] [Hide abstract] ABSTRACT: Microtubule dynamics is regulated by plus end-tracking proteins (+TIPs), which localize to the plus ends of microtubules (MTs). We previously showed that TACC1 and TACC3, members of the transforming acidic coiled-coil protein family, can act as +TIPs to regulate MT dynamics in Xenopus laevis. Here we characterize TACC2 as a +TIP that localizes to MT plus ends in front of EB1 and overlapping with TACC1 and TACC3 in multiple embryonic cell types. We also show that TACC2 can promote MT polymerization in mesenchymal cells but not neuronal growth cones, thus displaying cell-type specifcity. Structure-function analysis demonstrates that the C-terminal region of TACC2 is both necessary and suffcient to localize to MT plus ends and promote increased rates of MT polymerization, whereas the N-terminal region cannot bind to MT plus ends but can act in a dominant-negative capacity to reduce polymerization rates. Finally, we analyze mRNA expression patterns in Xenopus embryos for each TACC protein and observe neural enrichment of TACC3 expression compared with TACC1 and TACC2, which are also expressed in mesodermal tissues, including somites. Overall these data provide a novel assessment of all three TACC proteins as a family of +TIPs by highlighting the unique attributes of each, as well as their collective characteristics.
    Full-text · Article · Aug 2016
    • "An association between TACC2 expression and worse prognosis was also shown in the prostate cancer [10] and infant acute lymphoblastic leukemia [26] . Little information is available about association between TACC2 and resistance to adjuvant therapy, however, Takayama et al. showed that TACC2 contributed to hormone-refractory proliferation in prostate carcinoma [10]. Previous studies have also demonstrated that TACC1 was involved in endocrine therapy (tamoxifen and fulvestrant) resistance in breast cancer [27] and TACC3 was associated with chemoresistance (paclitaxel) in uterine cervical cancer [9]. "
    [Show abstract] [Hide abstract] ABSTRACT: Transforming acidic coiled-coil protein 2 (TACC2) belongs to TACC family proteins and involved in a variety of cellular processes through interactions with some molecules involved in centrosomes/microtubules dynamics. Mounting evidence suggests that TACCs is implicated in the progression of some human malignancies, but significance of TACC2 protein in breast carcinoma is still unknown. Therefore, in this study, we examined the clinical significance of TACC2 in breast carcinoma and biological functions by immunohistochemistry and in vitro experiments. Immunohistochemistry for TACC2 was performed in 154 cases of invasive ductal carcinoma. MCF-7 and MDA-MB-453 breast carcinoma cell lines were transfected with small interfering RNA (siRNA) for TACC2, and subsequently, cell proliferation, 5-Bromo-2'-deoxyuridine (BrdU), and invasion assays were performed. TACC2 immunoreactivity was detected in 78 out of 154 (51%) breast carcinoma tissues, and it was significantly associated with Ki-67 LI. The immunohistochemical TACC2 status was significantly associated with increased incidence of recurrence and breast cancer-specific death of the patients, and multivariate analyses demonstrated TACC2 status as an independent prognostic factor for both disease-free and breast cancer-specific survival. Subsequent in vitro experiments showed that TACC2 significantly increased the proliferation activity of MCF-7 and MDA-MB-453. These results suggest that TACC2 plays an important role in the cell proliferation of breast carcinoma and therefore immunohistochemical TACC2 status is a candidate of worse prognostic factor in breast cancer cases.
    Full-text · Article · Jun 2016
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